The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
75 巻, 4 号
選択された号の論文の19件中1~19を表示しています
  • Katsuhiko Ito, Yi-Zhun Zhu, Yi-Chun Zhu, Peter Gohlk, Thomas Unger
    1997 年 75 巻 4 号 p. 311-318
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    Angiotensin converting enzyme (ACE) is identical with kininase II. Besides reducing the production of angiotensin II, inhibition of ACE potentiates the biological actions of endogenous kinins. In hypertension-induced left ventricular hypertrophy, potentiation of endogenous kinins contributes to the improvement of cardiac function and energy metabolism and to capillary proliferation effected by ACE inhibitors. In myocardial infarction (MI), the potentiation of kinins has been shown to be involved in the reduction of infarct size and improvement of cardiac function by ACE inhibition. The cardioprotective actions of ACE inhibition in MI seem to be, in part, mediated by the augmentation of myocardial blood flow, especially in the ischemic region of the heart.
  • Yasuhiro Nakagami, Hiroshi Saito, Norio Matsuki
    1997 年 75 巻 4 号 p. 319-326
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    Neurotrophic effects in vitro have been generally related to promotion of differentiation, maturation and survival, but little is known about the effect on neuronal circuit formation. The organotypic culture system would be an available technique to investigate neuronal circuit formation and neuronal cell-cell interactions. As we reported previously, an optical recording system is a useful technique to comprehend neuronal activities and circuit from multi-points simultaneously. In this study, we investigated whether continuous application of basic fibroblast growth factor (bFGF or FGF-2) and brain-derived neurotrophic factor (BDNF) inhibited neuronal cell death induced by serum-deprivation in organotypic culture using propidium iodide staining, and we analyzed effects of bFGF and BDNF on the formation of neuronal circuits using the optical recording system. Continuous application of bFGF or BDNF significantly protected the slices from neuronal death. Optical recording also demonstrated that addition of 10 ng/ml bFGF or 50 ng/ml BDNF enhanced optical signals in all hippocampal areas significantly. These data strongly suggest that bFGF and BDNF promote the formation of neuronal circuits as well as survival and that optical recording of organotypic hippocampal slices would be a useful technique that enables us to analyze neuronal circuit formation easily.
  • Norifumi Yonehara, Motohide Takemura, Masakazu Yoshimura, Katsuya Iwas ...
    1997 年 75 巻 4 号 p. 327-335
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    To elucidate the involvement of nitric oxide in spinal nociceptive processing, the correlation of thermal withdrawal latency with nitric oxide synthase-stained neurons in the rat lumbar dorsal horn was analyzed after adjuvant-induced inflammation. From 4 hr through 5 days after subcutaneous injection of complete Freund''s adjuvant into the hind paw, a marked thermal hyperalgesia was observed for heat stimulus applied to the affected region. NADPH-diaphorase and nitric oxide synthase-positive neurons increased significantly in the superficial layers of the dorsal horn ipsilateral to the inflamed hind paw at day 3 of adjuvant-induced inflammation. No change in NADPH-diaphorase-positive neurons was observed at 1 hr and 1 day of adjuvant-induced inflammation. The intravenous administration of Nω-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg), an inhibitor of nitric oxide synthase, significantly blocked the adjuvant-induced thermal hyperalgesia at day 3 of inflammation, but not at day 1; and it had no effect in non-inflamed rats. This anti-hyperalgesic effect of L-NAME at day 3 of inflammation was reversed by the prior administration of L-arginine (600 mg/kg, i.p.), a substrate of nitric oxide synthase. These data suggest that nitric oxide producing neurons in the spinal dorsal horn are involved in maintaining and facilitating the hyperalgesia associated with chronic nociception.
  • Atsuko Kita, Kiyomi Imano, Yasuhiro Seto, Ikuhisa Yakuo, Takashi Deguc ...
    1997 年 75 巻 4 号 p. 337-346
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    To clarify the properties of BL-2401 ((±)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressantlike activities after oral administration, along with their association with endogenous opioid systems. BL2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED50: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg), the antinociceptive effect being antagonized by naloxone hydrochloride. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significant but modest antinociception at higher doses (200 and 400 mg/kg). In addition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepressant-like effect in the mouse forced swimming test. As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 ((±)-3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid), selectively inhibited enkephalinase in vitro (IC50: 5.2 nM). Oral administration of BL-2401 to mice significantly inhibited the enkephalinase activity in the striatum and also potentiated the antinociceptive effect of (D-A1aSUP>2, Met5)-enkephalin given intracisternally. These findings indicate that BL-2401 is an orally active enkephalinase inhibitor and may produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems.
  • Manabu Fujita, Yasuo Yonetomi, Hiroshi Takeda, Naoki Nakagawa, Kazuhit ...
    1997 年 75 巻 4 号 p. 347-353
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    To examine the effects of a specific cysteinyl leukotriene (cysLT) antagonist, pranlukast, on allergic rhinitis, antigen-induced rhinitis in guinea pigs was modified by pretreatment with an cyclooxygenase inhibitor (indomethacin) followed by an H1-blocker (pyrilamine). Intranasal ovalbumin (OVA) administration in actively sensitized guinea pigs resulted in concentration-dependent increases in nasal permeability and nasal airway resistance (NAR). Although pyrilamine (1 mg/kg, i.v.) abolished these antigen-induced changes, pretreatment with indomethacin (5 mg/kg, i.v.) followed by pyrilamine enhanced these responses to a degree similar to that observed with OVA challenge alone. Analyses of nasal perfusate in indomethacin/pyrilamine-pretreated animals showed that cysLTs increased by 270.8%, whereas thromboxane B2 decreased by 88.3% as compared with those on challenged with OVA alone. Oral administration of pranlukast (1-10 mg/kg) dose-dependently prevented increases in nasal permeability and NAR of indomethacin/pyrilamine-pretreated animals. However, an anti-allergic agent, azelastine, did not affect these responses. These results indicate that pranlukast suppresses antigen-induced cysLT-mediated responses of allergic rhinitis in actively sensitized guinea pigs. A cysLT antagonist, pranlukast, may thus prevent cysLT-mediated symptoms of allergic rhinitis.
  • Manabu Fujita, Naoki Nakagawa, Yasuo Yonetomi, Hiroshi Takeda, Kazuhit ...
    1997 年 75 巻 4 号 p. 355-362
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    To examine whether cysteinyl leukotrienes (cysLTs: LTC4, LTD4 and LTE4) induce symptoms of allergic rhinitis via their receptors, we studied the following: i) the specific binding of radiolabeled cysLTs to guinea pig nasal mucosa membrane and ii) effects of nasal LTD4 challenge in normal guinea pigs. The binding study indicated that there was a single population of binding sites for LTC4, LTD4 and LTE4 with Kd and Bmax values of 34.9±2.0, 0.252±0.015 and 0.589±0.039 nM and 10, 140±490, 122± 11 and 306±23 fmol/mg protein, respectively. The in vivo study showed that topical nasal challenge of LTD4 (0.1 30 μg/nose) increased nasal secretion, nasal airway resistance and nasal eosinophil infiltration without inducing sneezing. While the increases in nasal secretion and nasal airway resistance were transient, peaking 10 to 20 min after LTD4 challenge, nasal eosinophil infiltration persisted at least until 24 hr post-challenge. These nasal symptoms were dose-dependently suppressed by oral administrations of pranlukast (0.3-3 mg/kg). The results suggest that cysLTs cause not only early-phase symptoms but also nasal eosinophil migration, a characteristic associated with the late-phase symptom of allergic rhinitis, via a receptormediated mechanism. Cysteinyl leukotrienes, thus, may be important mediators in allergic rhinitis.
  • Takayuki Nagano, Yasuo Oyama, Noriko Kajita, Lumi Chikahisa, Mami Naka ...
    1997 年 75 巻 4 号 p. 363-370
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    Effects of new complex curcuminoids (cassumunin A and cassumunin B) isolated from tropical ginger, Zingiber cassumunar, were examined in dissociated rat thymocytes suffering from oxidative stress induced by 3 mM hydrogen peroxide by using a flow cytometer and ethidium bromide. The effects were compared with those of curcumin, a natural antioxidant, whose chemical structure is included in those of cassumunins A and B. Pretreatment of rat thymocytes with the respective cassumunins at concentrations ranging from 100 nM to 3 μM dose-dependently prevented the hydrogen peroxide (H202)-induced decrease in cell viability. It had the same action, although less effective, against the treatment with cassumunin A or B (3 μM) immediately after or 60 min after start of the oxidative stress. Respective potencies of cassumunins A and B in protecting the cells suffering from H202-induced oxidative stress were greater than that of curcumin. It is suggested that cassumunins A and B may possess a potent protective action on living cells suffering from oxidative stress.
  • Kenji Tobetto, Yumiko Yamamoto, Masanori Kataoka, Takao Ando, Kenji Su ...
    1997 年 75 巻 4 号 p. 371-379
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    M-5011 (d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid) is a newly developed nonsteroidal anti-inflammatory drug (NSAID) that displays potent anti-inflammatory and analgesic properties with low ulcerogenic activities in animal models. In this study, the effects of M-5011 on arachidonic acid (AA) metabolism in synovial fibroblasts from patients with rheumatoid arthritis were evaluated and compared with those of other NSAIDs in vitro. Either M-5011 or ketoprofen potently inhibited prostaglandin (PG) E2 production by cyclooxygenase (COX)-2 from exogenous AA in interleukin-1β (IL-1β)-stimulated cells. The IC50 values of M-5011 and ketoprofen were 4.4 x 10-7 and 5.9 × 10-7 M, respectively. However, diclofenac and indomethacin were one order less potent. Although the latter two drugs exhibited timedependent and irreversible inhibition on COX-2 in IL-1β-stimulated cells, the inhibitory effects of M-5011 and ketoprofen were reversible. PGE2 production by COX-1 from exogenous AA in non-stimulated cells was also inhibited by M-5011 with a potency less than that of ketoprofen. In addition, M-5011 inhibited [14C]AA release from prelabeled synovial cells stimulated with bradykinin. However, ketoprofen hardly affected the [14C]AA release. It is likely that the effects of M-5011 on AA metabolism are, in part, responsible for its in vivo efficacy and safety profile.
  • Tadashi Nagamatsu, Toshiyuki Nagao, Yosuke Nomura, Yoshio Suzuki
    1997 年 75 巻 4 号 p. 381-390
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    Immune complexes in glomeruli are involved in development of diverse glomerulonephritis. The disposal process of glomerular immune complexes has been unclarified. The present studies were undertaken to determine if thromboxane A2 (TXA2) is associated with the disposal of macromolecules in the glomeruli using mice injected with aggregated bovine serum albumin (a-BSA). A-BSA promptly accumulated in the glomeruli, the level reaching a plateau at 6 hr after the injection of a-BSA, and then decreased by 48 hr. The production of glomerular TXA2, prostaglandin E2 (PGE2) and prostaglandin I2 concomitantly increased with the decrease of a-BSA in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists accelerated clearance of glomerular a-BSA without enhancing renal tissue blood flow. They did not affect a-BSA level in the plasma. In contrast, aminophylline, dopamine and mannitol significantly increased renal tissue blood flow, but did not decrease glomerular a-BSA. TXA2 synthase inhibitors decreased TXA2 production in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists did not influence the generation of PGE2. The TXA2 analogue U-46619 significantly increased the accumulation of a-BSA in the glomeruli. We propose that TXA2 interferes with the disposal process of aggregated protein in the glomeruli. We also postulate that interception of glomerular activity of TXA2 may be an effective intervention for managing immune complex-mediated glomerulonephritis and glomerulosclerosis.
  • Koji Nishizawa, Akira Yamashita
    1997 年 75 巻 4 号 p. 391-397
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    he effects of Kamikihi-To (KMK), a traditional Chinese medicine, on behavioral changes induced by methyl-β-carboline-3-carboxylate (β-CCM) were evaluated in mice and rats. β-CCM, an anxiogenic benzodiazepine receptor inverse agonist (3.0 mg/kg, i.v. administered 1 min before the test), decreased the locomotor activity of mice in a novel environment. Furthermore, β-CCM (0.1 mg/kg, i.v. administered 10 min before the test) facilitated the suppression of drinking behavior induced by punishment in the water lick conflict test in rats. KMK (1.0 and 2.0 g/kg, p.o. administered 1 hr before the test) antagonized the decreased locomotor activity in the β-CCM-treated mice. KMK (2.0 g/kg, p.o.) also recovered the suppression of drinking behavior in the β-CCM-treated rats. KMK (2.0 g/kg, p.o.) had no effect on β-CCM-untreated mice and rats in these tests. These findings suggest that KMK has a protective effect against β-CCM-induced behavioral changes.
  • Yoshio Kase, Terumasa Hayakawa, Yuji Togashi, Tetsuya Kamataki
    1997 年 75 巻 4 号 p. 399-405
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    For characterization of the mechanism(s) of severe diarrhea due to the anticancer agent, irinotecan hydrochloride (CPT-11), examination was made of the relation of CPT 11 -related diarrhea to colonic prostaglandin E2 (PGE2) and water absorption in rats. Acute diarrheal symptoms were observed within 1 hr after the administration of CPT-11 to rats, with increased PGE2 and decreased water absorption in the colon. Treatment with atropine at 1 mg/kg, s.c. was noted to inhibit intestinal PGE2 and the CPT11-related acute diarrheal symptoms, indicating that these diarrheal symptoms were mediated through the cholinergic nervous system accelerated functionally by CPT-11. On the other hand, daily treatment of CPT-11 at the same dose resulted in chronic diarrheal symptoms in all animals 3 days after CPT-11 treatment. Histopathological changes observed in the descending colon and ileum of the rats included degeneration and necrosis of villi and cryptal cells and a decrease in the number of the goblet cells. Significantly increased PGE2 and impaired water absorption of the descending colon were also observed during the chronic diarrheal stage. It can be considered that the chronic diarrheal symptoms appear as a consequence of the gastrointestinal injury characterized by significant increase in PGE2 accompanied by impaired water absorption.
  • Yoshio Kase, Terumasa Hayakawa, Masaki Aburada, Yasuhiro Komatsu, Tets ...
    1997 年 75 巻 4 号 p. 407-413
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    The possible preventive effect of Kampo medicine Hange-shashin-to (TJ-14) on chronic diarrheal symptoms induced by the administration of the anticancer agent irinotecan hydrochloride (CPT-11) was investigated in the rat. Repeated oral administrations of TJ-14 at 125 and 500 mg/kg significantly prevented the reduction in body weight and the onset of chronic diarrheal symptoms due to CPT-11 in a dose-dependent manner, even though it failed to show a definite effect on acute diarrheal symptoms. In addition, treatment with TJ-14 accelerated the healing of the intestinal tract injured by repeated dosing of CPT-11 and inhibited significantly the increase of colonic prostaglandin E2 (PGE2) which is closely related to the onset of diarrhea. TJ-14 also improved colonic water absorption impaired by repeated dosing of CPT-11 in rats. These results demonstrate that TJ-14 is an effective medicine for the prevention and/or treatment of CPT-11-induced chronic diarrheal symptoms.
  • Hideyuki Funato, Hiroyuki Kawano, Yasushige Akada, Yukio Katsuki, Masa ...
    1997 年 75 巻 4 号 p. 415-423
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    We investigated the effects of lacidipine on focal cerebral ischemia in rats, and these effects were compared with those of nicardipine. Drugs were administered orally 5 min after middle cerebral artery occlusion (MCAO). Neurological scores as described by Bederson et al. (Stroke 17, 472-476, 1986) and cerebral infarct size (CIS) determined by the 2, 3, 5-triphenyltetrazolium chloride staining method were measured 24 hr after MCAO. Cerebral blood flow (CBF) and energy metabolites were determined by the hydrogen clearance method and an enzymatic method, respectively. In the drug-untreated group, we observed low-CBF of approximate 13 ml/ 100 g/min during 0.5-6 hr of occlusion and extensive cerebral infarction associated with severe neurologic deficits (ND). Lacidipine at 1 and 3 mg/kg, although it lowered blood pressure, improved low-CBF to approximate 20 ml/ 100 g/min during 1.5 6 hr of occlusion and increased tissue levels of ATP 6 hr after MCAO in a dose-dependent manner. Nicardipine at 30 mg/kg also improved low-CBF and increased tissue levels of ATP significantly. However, the improvement of low-CBF by nicardipine was transient. Lacidipine at 3 mg/kg reduced CIS and ameliorated ND significantly. In contrast, nicardipine at 30 mg/kg could not ameliorate ND in spite of a significant reduction of CIS similar to that of lacidipine (3 mg/kg). These results suggest that the improvement of focal cerebral ischemia by lacidipine may be partly due to long-lasting improvement of collateral blood supply to the ischemic area.
  • Manabu Okumura, Hirofumi Kai, Shinya Shinozawa, Yoichiro Isohama, Kazu ...
    1997 年 75 巻 4 号 p. 425-432
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    We have previously reported that activated eosinophils enhanced the phosphatidylcholine (PC) secretion in type II pneumocytes. In this study, we have determined whether xanthine derivatives affect the PC secretion increased by activated eosinophils. Theophylline enhanced the increased PC secretion at 10-5 M. 8-Phenyltheophylline dose-dependently enhanced the PC secretion. The enhanced secretion by either theophylline at 10-5 M or 8-phenyltheophylline was suppressed by superoxide dismutase in combination with catalase. Pentoxifylline did not enhance the PC secretion increased by activated eosinophils, although it increased the PC secretion by itself. The PC secretion increased by theophylline at 10-3 M or pentoxifylline was not suppressed by superoxide dismutase in combination with catalase. The present results suggest that xanthine derivatives increased the PC secretion in the co-culture of type II pneumocytes and activated eosinophils possibly through the inhibition of phosphodiesterases or the antagonism of adenosine receptors of the eosinophils.
  • Kazuho Abe, Hiroshi Saito
    1997 年 75 巻 4 号 p. 433-438
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    When cultured astrocytes are treated with agents that elevate intracellular cyclic AMP, they become process-bearing stellate cells. In the present study, we investigated possible developmental changes of astrocyte stellation induced by β-adrenoceptor stimulaton. Cultured astrocytes were prepared from the cerebral cortices of embryonic day 18 (E18) and postnatal day 2 (P2) rats. Treatment with the β-adrenoceptor agonist isoproterenol induced stellation in P2 astrocytes more potently and rapidly than in E18 astrocytes. Isoproterenol-stimulated increase in cellular cyclic AMP levels was very similar in E18 and P2 astrocytes. The membrane-permeable cyclic AMP analog dibutyryl cyclic AMP induced stellation in P2 astrocytes more potently and rapidly than in E18 astrocytes. Stellation induced by the protein kinase C activator phorbol ester was not different between E18 and P2 astrocytes. These results suggest that β-adrenoceptor-mediated astrocyte stellation increases during development and that this change is attributed to the development of mechanisms downstream from cyclic AMP production.
  • Shusheng Tai, Hirofumi Kai, Tomoyuki Kido, Yoichiro Isohama, Kazuo Tak ...
    1997 年 75 巻 4 号 p. 439-442
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    We investigated the effect of human neutrophil elastase (HNE) on tracheal mucociliary transport in anesthetized quails. Topical application of HNE (30-300 μg/kg) to tracheal mucosa dosedependently decreased mucociliary transport velocity (MCTV). The HNE (300 μg/kg)-induced decrease in MCTV was blocked by ONO-5046·Na (sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenyl-sulfonylamino]benzoyl]aminoacetate tetrahydrate) (3-30 mg/kg, i.m.), a specific neutrophil elastase inhibitor. Furthermore, we found that HNE increased DNA, fucose and protein contents of tracheal lavages, and the increases were also reverted by ONO-5046·Na. These results indicated that HNE decreased tracheal mucociliary transport, and the decrease may be, at least in part, ascribed to the deterioration of tracheal secretions.
  • Yukihisa Murakami, Emiko Tanaka, Yoshiyuki Sakai, Kinzo Matsumoto, Hon ...
    1997 年 75 巻 4 号 p. 443-446
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    Effect of tacrine, a cholinesterase inhibitor, on spatial acquisition deficit caused by permanent occlusion of bilateral common carotid arteries (2VO) was examined by using the conventional 8-arm and the 4-arm baited radial maze tasks in rats. Daily administration of tacrine (0.1 and 0.3 mg/kg, i.p.) 1 month after 2VO operation significantly improved the impaired spatial acquisition in the conventional maze task. This treatment also ameliorated the 2VO-induced working but not reference memory deficit in the 4arm baited radial maze task. These results suggest that tacrine improvement of working memory deficit in the 2VO rats is due to stimulation of central cholinergic systems.
  • Masayoshi Furushiro, Satoru Suzuki, Yoshiyuki Shishido, Masashi Sakai, ...
    1997 年 75 巻 4 号 p. 447-450
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    Soybean lecithin transphosphatidylated phosphatidylserine (SB-tPS) was investigated for its effect on the impaired learning of a passive avoidance task by mice induced by scopolamine or cycloheximide. SB-tPS (240, 360, 480 mg/kg) administered orally significantly prolonged the step-through latency shortened by scopolamine. SB-tPS (240 mg/kg) administered orally also prolonged the step-through latency shortened by cycloheximide. These results suggest that the effect of SB-tPS on the impaired learning behavior may be related not only to the cholinergic system but also the serotonergic system.
  • Santi Prasad Sinha Babu, Debapriya Sarkar, Naba Kumar Ghosh, Arpita Sa ...
    1997 年 75 巻 4 号 p. 451-454
    発行日: 1997年
    公開日: 2006/03/27
    ジャーナル フリー
    Acaciaside A and B, two acylated triterpenoid bisglycosides isolated from the funicles of Acacia auriculiformis, are known to have antihelmintic activity. Since the saponins contain a conjugated unsaturated system that is highly susceptible to peroxidation, we investigated the interaction of saponins and membrane using rat liver microsomes as our model. Microsomal membranes were incubated with saponins at 30°C for 2 hr. Following incubation, lipid peroxidation was measured in terms of malondialdehyde and conjugated diene. Our results showed that incubation of microsomal membranes with saponins increased both malondialdehyde and conjugated diene. The results suggest that in our model, saponins enhance the membrane lipid peroxidation.
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